Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss-of-function mutations in Patched (Ptch1) are implicated in constitutive activation of the Sonic hedgehog pathway in human basal cell carcinomas (BCCs), and inherited Ptch1 mutations underlie basal cell nevus syndrome in which a typical feature is multiple BCC occurring with greater incidence in portals of radiotherapy. Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with basal cell nevus syndrome. We therefore examined BCC development in control and irradiated Ptch1(neo67/+) mice. We show that unirradiated mice develop putative BCC precursor lesions, i.e., basaloid hyperproliferation areas arising from both follicular and interfollicular epithelium, and that these lesions progress to nodular and infiltrative BCCs only in irradiated mice. Data of BCC incidence, multiplicity, and latency support the notion of epidermal hyperproliferations, nodular and infiltrative BCC-like tumors representing different stages of tumor development. This is additionally supported by the pattern of p53 protein expression observed in BCC subtypes and by the finding of retention of the normal remaining Ptch1 allele in all nodular, circumscribed BCCs analyzed compared with its constant loss in infiltrative BCCs. Our data suggest chronological tumor progression from basaloid hyperproliferations to nodular and then infiltrative BCC occurring in a stepwise fashion through the accumulation of sequential genetic alterations.
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PMID:Basal cell carcinoma and its development: insights from radiation-induced tumors in Ptch1-deficient mice. 1487 23

We present an unusual case of cutaneous carcinosarcoma with the epithelial component closely resembling nodular basal cell carcinoma, and the mesenchymal component composed of cells constituting extended follicular papillae. A solitary tumor was excised in an 80-year-old man. Histologic sections revealed an ulcerated, asymmetric, poorly circumscribed neoplasm composed of epithelial cells arranged in lobules with peripheral palisading or in a cribriform pattern. The epithelial cells were darkly basophilic with scant cytoplasm and round or oval nuclei with an indistinct chromatin pattern and nucleoli. Nuclei crowding and mitotic figures were observed. Some lobules contained melanin. There were no shadow cells, sebaceous or apocrine glandular differentiation. Each epithelial nodule was surrounded by multiple rows of cells with pale vesicular nuclei and scant cytoplasm. Smaller epithelial aggregations were encircled by these cells concentrically; in larger ones these cells were aligned across a broad front resembling so-called "continuous papillae". Additionally, numerous small follicular germ-like structures associated with papillae were seen. The cells composing "continuous papillae" showed nuclear pleomorphism, numerous mitotic figures including atypical ones, and nuclear crowding. At foci, the transition from the multilayered arrangement of these cells into their diffuse proliferation in the stroma was seen. There were no transitions between the epithelial and stromal component; both were intermingled as though being mutually dependent, with no areas revealing a high-grade tumor or dedifferentiation. Immunohistochemically, the epithelial cell component stained with cytokeratins. The cells of the mesenchymal component tested positive for vimentin and negative for desmin and cytokeratins. The proliferation index (Ki-67) was high in both components. There were also a high number of p53-positive cells in both compartments. We propose the term "low-grade trichoblastic carcinosarcoma" for this neoplasm. We are not aware of a similar tumor published in the English literature.
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PMID:Low-grade trichoblastic carcinosarcoma of the skin. 1524 61

Imiquimod is an immune-response modifier that has been shown to be effective in the treatment of superficial and nodular basal cell carcinoma (BCC). The objective of this open-label study was to investigate the effectiveness of imiquimod 5% cream in superficial, nodular, and infiltrative BCC. Fifty-five Caucasian patients with primary BCC measuring 8 mm or more in diameter with a superficial, nodular, or infiltrative histological pattern were included in the study. Four groups of BCC (A, B, C, and D) and two dosing regimens were studied: 35 BCCs (groups A, B, and C) were treated with imiquimod three times weekly and 20 BCCs (group D) were treated with imiquimod five times weekly. Histological samples were obtained before treatment, during treatment (on day 22 in group A, day 15 in group B, and day 8 in groups C and D), and 6 weeks after treatment. All patients were followed-up for a minimum of 2 years. In the biopsy specimens obtained, the expression of Bcl-2, p53, and Ki-67, apoptotic index (Tunel technique), and the number of CD3+, CD8+, CD20+, CD56+, CD68+, granzyme B+, and S-100+ cells in the peritumoural inflammatory infiltrate, were determined and quantified. Of the 55 BCCs treated with imiquimod 41 (74%) were in complete remission after 2 years of follow-up. These comprised 4/4 superficial BCCs, 7/8 (88%) nodular BCCs, and 30/43 (70%) infiltrative BCCs. Multi-variate analysis demonstrated that baseline tumour size was the most powerful independent prognostic variable (P < 0.05). Treatment with imiquimod increased the apoptotic index (P < 0.05), reduced Bcl-2 expression (P < 0.05), and increased the number of CD3+, CD8+, CD20+, CD68+, granzyme B+, and S-100+ cells in the inflammatory infiltrate of the BCC (P < 0.05). In conclusion, imiquimod induced an antitumour immune response mediated by lymphocytes and macrophages, reduced Bcl-2 expression and increased the apoptotic index of BCC, and was clinically effective in 74% of BCCs after a 2-year follow-up period.
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PMID:Open study of the efficacy and mechanism of action of topical imiquimod in basal cell carcinoma. 1534 39

Foci of normal keratinocytes overexpressing p53 protein are frequently found in normal human skin. Such epidermal p53 clones are common in chronically sun-exposed skin and have been suggested to play a role in skin cancer development. In the present study, we have analyzed the prevalence of p53 mutations in epidermal p53 clones from normal skin surrounding basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Using laser-assisted microdissection, 37 epidermal p53 clones adjacent to BCC (21) and SCC (16) were collected. Genetic analysis was performed using a multiplex/nested polymerase chain reaction followed by direct DNA sequencing of p53 exons 2-11. In total, 21 of 37 analyzed p53 clones consisted of p53-mutated keratinocytes. The identified mutations were located in p53 exons 4-8, corresponding to the sequence-specific DNA-binding domain. All mutations were missense, and 78% displayed a typical ultraviolet signature. The frequency of p53 mutations was similar in skin adjacent to BCC compared to SCC. The presented data confirm and extend previous knowledge on the genetic background of epidermal p53 clones. The mutation spectra found in epidermal p53 clones resemble that of non-melanoma skin cancer. Approximately, 40% of the epidermal p53 clones lacked an underlying p53 mutation, suggesting that other genetic events in genes up- or downstream of the p53 gene can generate foci of normal keratinocytes overexpressing p53 protein.
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PMID:Mutation spectra of epidermal p53 clones adjacent to basal cell carcinoma and squamous cell carcinoma. 1544 25

Recent advances in molecular genetics have led to a better understanding of the biological underpinnings of skin cancer formation. As with most cancers, the RB, p53, and RAS pathways appear to play prominent roles in the pathogenesis of several skin cancer types. Although various components of these pathways may be differentially altered in squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma, the final biochemical expression of these defects may be the same. With the unraveling of these genetic mechanisms, a more targeted approach to diagnosis and treatment may be possible in the near future.
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PMID:The genetics of skin cancer. 1546 70

Post-transcriptional modification of p53 by phosphorylation has been proposed as an important mechanism of p53 stabilization and functional regulation. However, little is known about the phosphorylation state of mutant p53 protein overexpressed in human tumors. We evaluated immunohistochemically the p53 phosphorylation state of Ser392 and Ser15 sites in 44 actinic keratoses (AKs), 62 squamous cell carcinomas (SCCs), 23 Bowen's disease (BDs) and 43 basal cell carcinomas (BCCs). The mean labeling index (LI) of phospho-Ser392-p53 was significantly higher than that of phospho-Ser15-p53 in all cases. Phospho-Ser392-p53 protein was frequently overexpressed in not only SCCs but also AKs and BDs, revealing no significant difference in the immunoreactivity among them. In BCCs, phospho-Ser392-p53 immunoreactivity was significantly lower than that in BDs, and phospho-Ser15-p53 immunoreactivity was significantly lower than that in SCCs. Ser15 phosphorylation was significantly correlated with a high level of Ki-67 LI in BCCs. These results suggest that p53 overexpressed in skin tumors is more frequently phosphorylated at Ser392 residue than Ser15, and that the Ser392 phosphorylation is more likely to occur early in the pathogenesis of SCC. Moreover, the decreased level of the phosphorylation might be characteristic of BCC, but the Ser15 phosphorylation seems to have an influence on BCC development.
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PMID:Phosphorylation state of tumor-suppressor gene p53 product overexpressed in skin tumors. 1549 90

Carcinogenesis is a multi-step series of somatic genetic events. The complexity of this multi-hit process makes it difficult to determine each single event and the definitive outcome of such events. To investigate the genetic alterations in cancer-related genes, sensitive and reliable detection methods are of major importance for generating relevant results. Another critical issue is the quality of starting material which largely affects the outcome of the analysis. Microdissection of cells defined under the microscope ensures a selection of representative material for subsequent genetic analysis. Skin cancer provides an advantageous model for studying the development of cancer. Detectable lesions occur early during tumor progression, facilitating molecular analysis of the cell populations from both preneoplastic and neoplastic lesions. Alterations of the p53 tumor suppressor gene are very common in non-melanoma skin cancer, and dysregulation of p53 pathways appear to be an early event in the tumor development. A high frequency of epidermal p53 clones has been detected in chronically sun-exposed skin. The abundance of clones containing p53 mutated keratinocytes adjacent to basal cell (BCC) and squamous cell carcinoma (SCC) suggests a role in human skin carcinogenesis. Studies using p53 mutations as a clonality marker have suggested a direct link between actinic keratosis, SCC in situ and invasive SCC. Microdissection-based studies have also shown that different parts of individual BCC tumors can share a common p53 mutation yet differ with respect to additional alterations within the p53 gene, consistent with subclonal development within tumors. Here, we present examples of using well-defined cell populations, including single cells, from complex tissue in combination with molecular tools to reveal features involved in skin carcinogenesis.
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PMID:Genetic tumor archeology: microdissection and genetic heterogeneity in squamous and basal cell carcinoma. 1574 39

Pinkus described "pre-malignant fibroepithelioma" as a proliferation that gave rise to many tiny basal cell carcinomas within each lesion. Later authors have generally considered it to be an unusual variant of basal cell carcinoma (BCC). The delineation of trichoblastoma as the general term for the benign counterpart of BCC raises the possibility that the fibroepithelioma of Pinkus (FEP) would be better classified under that rubric. To address this subject, we examined the records of 114 patients with FEP for body site, age and sex distribution, and sections from 75 lesions. All FEP examined show a blunt interface with the underlying dermis (where one could be seen), differentiation toward follicular bulbs and papillae, and large areas of cellular stroma. FEP has a slight female preponderance in contrast to BCC, which is more common in males. Unlike the common types of BCC, FEP has an overwhelming predilection for the trunk and extremities, and only 5% of tumors are set in a dermis with significant amounts of solar elastosis. Next, FEP, BCC, and FEP with BCC-like areas were stained with MIB-1 (to assess proliferation), p53 (an oncogene product), and CK20 (a Merkel cell marker) antisera. FEP shows a low level of staining for p53 and MIB-1, in contrast to conventional BCCs that over-express these markers. FEP also shows retention of Merkel cells, a characteristic of benign neoplasms with follicular germinative differentiation but not in general of BCC. The BCC-like areas in some FEP tumors reflect these staining tendencies with less striking differences. Given the contrast between FEP and BCC with respect to site of occurrence, relationship to sun damage, histopathologic features, and immunohistochemical studies, it appears that FEP more closely resembles trichoblastoma than BCC.
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PMID:Fibroepithelioma of pinkus is a fenestrated trichoblastoma. 1579 42

Microsatellite instability (MSI) constitutes an alternative-to the chromosomal instability-pathway of carcinogenesis for certain tumour types with prognostic and therapeutic significance for the respective patients. MSI is caused by mutations in mismatch repair (MMR) genes, mainly hMLH1, hMSH2, leading to a defective MMR system. The role of MSI in basal cell carcinoma (BCC) has not been clearly delineated yet. p53 gene as a target for ultraviolet radiation-induced mutations may enhance genomic instability in BCC, with loss of its function. Our aim was to investigate the involvement of MSI and expression of hMLH1 and hMSH2 in parallel with P53 protein accumulation in the pathogenesis of BCC and its possible correlation to the clinicopathological features of the patients. The presence of MSI was investigated in 76 BCCs using mononucleotide microsatellite markers, BAT-25, BAT-26 and TGF-beta receptor type II (TGF-beta-RII). Additionally, 3 dinucleotide markers were analysed in 20 cases in which matched normal tissue was available. The expression of hMLH1, hMSH2 and P53 proteins was evaluated by immunohistochemical analysis. Alterations of the BAT-26 marker were observed in one fibroepithelioma of Pincus, one nodular and one multifocal superficial BCC. A keratotic BCC showed an altered BAT-25 locus. Two samples, a multifocal superficial and a nodular BCC, displayed MSI at two markers (BAT-25 and BAT-26; and BAT-25 and TGF-beta-RII, respectively). Three more cases, a metatypical, a multifocal superficial and a signet ring BCC exhibited frameshift mutations in the TGF-beta-RII. No sample showed length alterations at the dinucleotide markers examined. hMLH1 and hMSH2 protein immunohistochemical expression was scored positive in 46 and 49 out of 52 cases respectively. P53 accumulation was observed in 27 out of 56 samples. Correlation of the molecular and immunohistochemical findings with the clinicopathological parameters produced no statistically significant results. No correlation between MSI and hMLH1, hMSH2 or P53 protein expression was determined. MSI appears to play a minor role in the pathogenesis of BCCs being present only in a small subset of such tumours.
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PMID:Expression of mismatch repair enzymes, hMLH1 and hMSH2 is not associated with microsatellite instability and P53 protein accumulation in basal cell carcinoma. 1601 76

Long-term ultraviolet-light (UV) exposure of human skin epidermis is associated with an increased risk for the development of skin cancers, such as melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). UV radiation not only induces DNA damage in epidermal cells, it also interferes with skin homeostasis, which is maintained by a unique distribution pattern of apoptosis-inducing and -preventing molecules. If the DNA damage is not repaired or the damaged cells are not eliminated by apoptosis, the consequence can be cell transformation, uncontrolled proliferation and eventually skin tumor formation. An important "repair" gene is the p53 suppressor gene. Excessive UV exposure can mutate the p53 gene leading to the loss of its repair function and thus apoptosis resistance of the DNA-damaged cell. For BCC formation an additional pathway has been identified. Mutation of genes of the Hedgehog signaling pathway evokes the downregulation of apoptotic genes and upregulation of anti-apoptotic genes preventing the elimination of damaged cells. In addition, BCC and SCC strongly express the apoptosis-inducing Fas-ligand (FasL) which may help the tumor to escape the attack of immune effector cells. Silencing the genes involved in tumor formation by RNA interference might become a promising new approach to treat skin tumors.
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PMID:Role of apoptosis in basal cell and squamous cell carcinoma formation. 1605 33


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